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GB2069493A - Pyridine derivatives - Google Patents

Pyridine derivatives Download PDF

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Publication number
GB2069493A
GB2069493A GB8104413A GB8104413A GB2069493A GB 2069493 A GB2069493 A GB 2069493A GB 8104413 A GB8104413 A GB 8104413A GB 8104413 A GB8104413 A GB 8104413A GB 2069493 A GB2069493 A GB 2069493A
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GB
United Kingdom
Prior art keywords
acid addition
addition salt
compound
pyridine
methyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB8104413A
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GB2069493B (en
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John Wyeth and Brother Ltd
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John Wyeth and Brother Ltd
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Priority to GB8104413A priority Critical patent/GB2069493B/en
Publication of GB2069493A publication Critical patent/GB2069493A/en
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Publication of GB2069493B publication Critical patent/GB2069493B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention provides a compound of formula I <IMAGE> wherein R represents hydrogen, lower alkyl, aryl or aralkyl, R<1> represents hydrogen or lower alkoxy, R<2> represents hydrogen, chlorine or trifluoromethyl and n is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof, for use as a pharmaceutical. The compounds are particularly useful as anti-ulcer agents and pharmaceutical compositions containing them are covered. Novel compounds of formula I and methods for their preparation are also claimed.

Description

SPECIFICATION Pyridine derivatives The invention relates to pyridine derivatives which show activity in tests for anti-ulcer and/or antisecretory activity.
In our search for novel anti-ulcer agents we have found that certain 2-(arylthiomethyl) pyridine derivatives possess activity in tests for anti-ulcer or anti-secretory activity and hence are of value in the treatment of ulcers or hypersecretion in mammals. Some of these compounds are known chemicals others are novel.
Accordingly in its broadest aspect the invention provides as a pharmaceutical, e.g. an antiulcer agent, a compound of formula I
wherein R represents hydrogen, lower alkyl, aryl or aralkyl, R' represents hydrogen or lower alkoxy, R2 represents hydrogen, chlorine or trifluoromethyl and n is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof.
In this specification a lower alkyl group has from 1 to 6 carbon atoms e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl and n-hexyl. A loweralkoxy substituent is alkoxy in which the alkyl portion is as defined for a lower alkyl group. Whenever the term lower alkyl is used as part of another radical, e.g. arylloweralkyl, the lower alkyl or lower alkoxy portion has 1 to 6 carbon atoms unless otherwise stated.
The aryl group R is preferably phenyl or substituted phenyl, substitutents being halogen, lower alkyl, lower alkoxy and so on. Aralkyl is preferably phenyl lower alkyl.
The acid addition salts of compounds of formula I may be of an organic or inorganic acid, e.g.
hydrochloric, hydrobromic, phosphoric, sulphuric, nitric, citric, acetic, formic, fumaric, maleic, tartaric, embonic, methane sulphonic, and p-toluene sulphonic acids.
The compounds of formula I and their acid addition salts may be used in pharmaceutical compositions.
For the pharmaceutical compositions any suitable carrier known in the art can be used. In such a composition, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet disintegrating agents; it can also be encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 1 0-80% of the active ingredient.Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carriers which is thus in association with it. Similarly cachets are included.
Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil.
Preferably the pharmaceutical composition is in unit dosage form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 10 to 500 mg or more, e.g. 25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
The anti-ulcer compositions of the invention will be administered orally in either liquid or solid composition form. These compositions may include one or more antacid ingredients, e.g. aluminium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, calcium carbonate, magnesium trisilicate, sodium bicarbonate or the alumina gel described in British Specification No 1,284,394.
Anti-ulcer activity was determined by the stress-induced erosion test of Senay 8 Levine, Proc Soc Exp Biol Med, 124,1221-3(1967) and anti-secretory activity by the test of H Shay, D Sun and H Gruenstein, Gastroenterology, 1954,26, 903-13 as exemplified by Beattie et a/ J Med Chem 20, 714 (1977). Compounds which possess one or both these activities are considered to be anti-ulcer agents which can be used for the treatment of ulcers or hypersecretion in mammals. The compounds of formula I which we have tested possess one or both of the above activities.
Some compounds of the invention are novel and the invention also concerns novel compounds of formula Il
wherein R, R1, R2 and n are as defined in connection with formula I but at least one of R, R1 and R2 is other than hydrogen, and pharmaceutically acceptable acid addition salts thereof.
A compound of formula I wherein R, R1 and R2 are hydrogen and n is 1 is described in J. Org.
Chem. 1963,281323.
The invention includes a method of-preparing a novel compound of formula II, which method comprises reacting a thiol compound of formula Ill, or an alkali metal salt thereof.
wherein R' and R2 are as defined in connection with formula ll with a pyridine derivative of formula IV
wherein n is 1 or 2, R is as defined in connection with formula II and Hal is a halogen atom, especially chlorine, bromine or iodine and if desired converting the product to an acid addition salt.
The invention includes a method of treating ulcers or hypersecretion in a mammal, which method comprises administering to said mammal an effective amount of a compound of formula I or an acid addition salt thereof. The amount of compound used will depend on the activity of the compound and the needs of the mammal being treated. Doses may range from 1 to 100 mg/kg.
The invention is illustrated by the following Examples: EXAMPLE 1 2-((Phenylthio)methyl)pyridine Thiophenol (21 ml) was added to a solution of sodium (4.69) in ethanol (100ml). To the resulting solution was added 2-picolyl chloride, hydrochloride (15g) and the mixture was heated at reflux for 2 hours. Precipitated sodium chloride was removed by filtration and the solution was acidified with ethereal HCI. The solvent was removed by evaporation and the residue induced to crystallise by trituration with ether. Recrystallisation from ethanol-ether gave 2-((phenylthio)-methyl)pyridine, hydrochloride (5.0g) mp 1 42-40C (Found: C, 60.6; H, 5.25; N, 5.5 C12H11NS, HCI requires C, 60.6; H, 5.1; N, 5.9%).
This compound is also described in J Org Chem 1963, 28, 1-323.
EXAMPLE 2 2-(((4-Chlorophenyl)thio)methyl)pyridine 4-Chlorobenzenethiol (5g) in warm ethanol (5ml) was added to a solution of sodium hydroxide (2.8g) in ethanol (50ml). To the solution was added a solution of 2-picolyl chloride, hydrochloride (5.7g) in ethanol (25ml) and the mixture was stirred at ambient temperature for 6 hours.The mixture was filtered and evaporated and the residue was converted into the hydrochloride with ethereal HCI solution and this was recrystallised from ethanol-ether to give 2-(((4-chlorophenyl)thio)methyl)pyridine, hydrochloride (8g) mp 1 96-80C (Found: C, 52.95; H, 4.1; N, 5.15 C12H10CINS.HCI requires C, 53.1; H, 4.2; N, 4.9%) EXAMPLE 3 2-(((3-Trifluoromethylphenyl)thio)methyl)pyridine m-Trifluoromethylbenzenethiol (5g) was added to a solution of NaOH (2.25g) in ethanol (50ml) and the resulting solution was treated with a solution of 2-picolyl chloride, hydrochloride (4.69) in ethanol (25ml) and the mixture was stirred for 5 hours. The resulting suspension was filtered through kieselghur and the solvent was removed by evaporation.The residue was converted into the hydrochoride in ether with ethereal HCI and recrystallised from acetone-ether to give 2-(((3trifluoromethylphenyl)thio)methyl)-pyridine hydrochloride (4.8g) mp 1 45-60C Found: C, 51.1; H, 4.0; N, 4.7. C,3H10F3NS.HCI requires C, 51.0; H, 3.6; N, 4.6%).
EXAMPLE 4 2-(((2-Methoxyphenyl)thio) methyl)pyridine 2-Methoxybenzenethiol (5g) was added to a solution of sodium hydroxide (2.85g) in ethanol (50ml) and the resulting mixture was treated with 2-picolyl chloride, hydrochloride (5.79) in ethanol (25ml) at OOC. After 1 6 hours at ambient temperature the mixture was filtered through kieselghur and evaporated. The residue was converted into the hydrochloride in ether with ethereal HCI solution and this was recrystallised from propan-2-ol/acetone to give 2-(((2-methoxyphenyl)- thio)methyl)pyridine, hydrochloride (4.0g) mp 1 41-30C. (Found: C, 58.5; H, 5.4; N, 4.9 C13H13NOS.HCí requires C, 58.31 H.
5.3; N, 5.2%).
EXAMPLE 5 2-Methyl-6-((phenylthio) methyl)pyridine Following the method of Example 1 thiophenol is reacted with 6-methyl-2-picolyl chloride hydrochloride in the presence of sodium ethoxide to give the title compound.
Pharmaceutical Compositions The following examples illustrate the preparation of unit dosage form of pharmaceutical compositions according to the invention.
EXAMPLE A Antacid Tablet (chewable) Saccharin 1.0 mg Hydrated alumina sucrose powder 750.0 mg 2-((Phenylthio)methyl)pyridine 100.0 mg Mannitol BP 170.0 mg Maize starch BP dried 30.0 mg Talc purified BP 28.0 mg Magnesium stearate BP 20.0 mg Peppermint oil BP 1.0 mg 1 100.0 mg Antacid tablets of the above formulation are prepared by the following procedure. Triturate peppermint oil with talc (screen 40 mesh). Add the triturate, and other ingredients to a blender and mix thoroughly. Slug the powder to large hard slugs. Granulate the slugs through a 14 mesh screen.
Compress the granules on a suitable compression machine to give tablets of the required size.
EXAMPLE B Anti-ulcer tablet (without antacid) mg/tablet 2-((Phenylthio)methyl)pyridine, hydrochloride 100.0 mg Celutab 147.5 mg Mg Stearate 2.5 mg 250.0 mg The tablets are prepared by the following method. Blend the ingredients in a suitable blender.
Compress the blended ingredients on a suitable compression machine to form tablets of the above composition. Celutab is a commercial product comprising 902% dextrose, 3-5% maltose, the remainder being higher glucose saccharides. The product is spray crystallised.
EXAMPLE C Example A is repeated but replacing 2-((phenylthio)methyl) pyridine with 100 mg of 2-(((4 chlorophenyl)thio)methyl) pyridine.
EXAMPLE D Example B is repeated but replacing 2-((phenylthiomethyl)pyridine)hydrochloride with 100 mg of 2-(((4-chlorophenyl)thio)methyl)pyridine hydrochloride.
Pharmacological Test Results
Compound Stress-induced CProduct of etosion Anti-secretory Example Nol (Senay & levine) (Shay et al) Dose % Dose % change mg/ kg inhibition mg/ kg in vol 1 100 45 30 -46 2 100 NS 30 -69 3 100 NS 30 -19 4 100 56 30 -35 NS - not significant

Claims (19)

1. A compound of formula I
wherein R represents hydrogen, lower alkyl, aryl or aralkyl, R1 represents hydrogen or lower alkoxy, R2 represents hydrogen, chlorine or trifluoromethyl and n is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof, for use as a pharmaceutical.
2. A compound of formula I as claimed in Claim 1, wherein R is hydrogen or methyl, R1 is hydrogen or methoxy, R2 and n are as defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, for use as a pharmaceutical.
3. 2-((Phenylthio)methyl)pyridine, or an acid addition salt thereof, for use as a pharmaceutical.
4. 2-(((4-Chlornphenyl)thio)methyl)pyridine, or an acid addition salt thereof, for use as a pharmaceutical.
5. 2-(((3-Trifluoromethylphenyl)thio)methyl)pyridine, or a pharmaceutically acceptable acid addition salt thereof, for use as a pharmaceutical.
6. 2-(((2-Methoxyphenyl)thio)methyl)pyridine, or a pharmaceutically acceptable acid addition salt thereof, for use as a pharmaceutical.
7. A compound as claimed in any one of claims 1 to 6, for use as an anti-ulcer agent.
8. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 6, and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition as claimed in Claim 8, wherein the carrier includes an antacid ingredient.
10. A pharmaceutical composition as claimed in Claim 8 or Claim 9 in unit dosage form.
11. A pharmaceutical composition as claimed in Claim 8, substantially as hereinbefore described in any one of Examples A, B, C or D.
12. A compound of formula II
wherein R, R1, R2 and n are as defined in Claim 1 and at least one of R, R', and R2 is other than hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
13. 2-(((4-Chlorophenyl)thio)methyl)pyridine or a pharmaceutically acceptable acid addition salt thereof.
14. 2-(((3-Trifluoromethylphenyl)thio)methyl)pyridine or a pharmaceutically acceptable acid addition salt thereof.
1 5. 2-(((2-Methoxyphenyl)thio)methyl)pyridine or a pharmaceutically acceptable acid addition salt thereof.
16. A method for preparing a compound oaf formula 11, as claimed in Claim 12, which method comprises reacting a thiol compound of formula Ill
wherein R' and R2 are as defined in Claim 1, with a pyridine derivative of formula IV
wherein n is 1 or 2, R is as defined in connection with formula ll and Hal is a halogen atom, especially chlorine bromine or iodine, and if desired converting the product to an acid addition salt.
17. A method as claimed in Claim 16, wherein the compound prepared is a compound as claimed in Claim 13, Claim 14 or Claim 1 5.
1 8. A method as claimed in Claim 16, substantially as hereinbefore described in any one of Examples 2 to 4.
19. A compound of formula II or an acid addition salt thereof, whenever prepared by a method as claimed in any one of claims 1 6 to 18.
GB8104413A 1980-02-20 1981-02-12 Pyridine derivatives Expired GB2069493B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB8104413A GB2069493B (en) 1980-02-20 1981-02-12 Pyridine derivatives

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GB8005669 1980-02-20
GB8104413A GB2069493B (en) 1980-02-20 1981-02-12 Pyridine derivatives

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GB2069493A true GB2069493A (en) 1981-08-26
GB2069493B GB2069493B (en) 1984-02-29

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58203965A (en) * 1982-05-05 1983-11-28 ル−ド・ビツヒ・ホイマン・アンド・シ−オ−・ジ−エムビ−エイチ Thiomethylpyridine derivative, manufacture and medicinal composition
FR2578540A1 (en) * 1985-03-08 1986-09-12 Leo Pharm Prod Ltd NOVEL DERIVATIVES OF PYRIDYLMETHOXY- AND -METHYLMERCAPTOANILINES, USED IN PARTICULAR AS ANTIASTHMATICS, THEIR MANUFACTURE AND MEDICAMENTS CONTAINING SAME
EP0254611A1 (en) * 1986-06-25 1988-01-27 Roussel-Uclaf Derivatives of 8-phenylthiotetrahydroquinolines and their salts, their synthesis for use as medicaments and compositions containing them
EP0264883A3 (en) * 1986-10-21 1990-04-04 Banyu Pharmaceutical Co., Ltd. Substituted pyridine derivatives

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58203965A (en) * 1982-05-05 1983-11-28 ル−ド・ビツヒ・ホイマン・アンド・シ−オ−・ジ−エムビ−エイチ Thiomethylpyridine derivative, manufacture and medicinal composition
EP0093252A3 (en) * 1982-05-05 1984-08-22 Ludwig Heumann & Co Gmbh Thiomethylpyridine derivatives, process for their preparation and medicaments containing them
FR2578540A1 (en) * 1985-03-08 1986-09-12 Leo Pharm Prod Ltd NOVEL DERIVATIVES OF PYRIDYLMETHOXY- AND -METHYLMERCAPTOANILINES, USED IN PARTICULAR AS ANTIASTHMATICS, THEIR MANUFACTURE AND MEDICAMENTS CONTAINING SAME
EP0254611A1 (en) * 1986-06-25 1988-01-27 Roussel-Uclaf Derivatives of 8-phenylthiotetrahydroquinolines and their salts, their synthesis for use as medicaments and compositions containing them
EP0264883A3 (en) * 1986-10-21 1990-04-04 Banyu Pharmaceutical Co., Ltd. Substituted pyridine derivatives

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PE20 Patent expired after termination of 20 years

Effective date: 20010211